Pharmacological cardioprotective strategy for non-metastatic patients affected by breast cancer receiving an anthracycline-based chemotherapy: Final results of the phase 3 SAFE trial.
Authors: Lorenzo Livi, Giuseppe Barletta, Francesca Martella, Calogero Saieva, Carlotta Becherini, Carlotta Bacci, Maria Riccarda Del Bene, Mario Airoldi, Domenico Amoroso, Luigi Coltelli, Giuseppe Pilato, Luca Visani, Viola Salvestrini, Fulvia Pedani, Marco Bernini, Lorenzo Orzalesi, Jacopo Nori, Simonetta Bianchi, Iacopo Olivotto, Icro Meattini
Journal: Journal of Clinical Oncology (2023)

12079 Background: Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue. We aim to determine whether pharmacological cardiac prevention could reduce subclinical heart damage in breast cancer (BC) patients treated with anthracycline-based chemotherapy. Methods: The SAFE trial is a four-arm, randomised, phase 3, double-blind, placebo-controlled study. Patients were eligible for trial inclusion if they had indication to primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with prior diagnosis of cardiovascular disease were excluded. Cardioprotective therapy (bisoprolol (B), ramipril (R), or both drugs (B+R), as compared to placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of HER2 positive patients. Doses for all groups were systematically up-titrated, up to the daily target dose of B (5 mg, once daily), R (5 mg, once daily), and placebo, if tolerated. The primary endpoint was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Results: 262 women (median 48 years; range24-75 years) were enrolled and treated in the study. We analysed patients who had completed the pre-planned cardiological assessment at 24 months. All patients received an anthracycline-based chemotherapy, 215 patients received at least 3 cycles of anthracyclines (range 1-6) and 128 patients had postoperative radiation therapy. At Univariate logistic analysis to evaluate the risk of GLS worsening &gt; 10% at 24 months, Odds ratios (OR) for improvement were 0.055, 0.083 and 0.060 for B, R and B+R, respectively (P &lt; 0.0001), if compared to placebo arm. At Univariate logistic analysis to evaluate the risk of 3DLVEF worsening &gt; 10% at 24 months, OR for improvement were 0.019, 0.048 and 0.054 for B, R and B+R, respectively (P &lt; 0.0001), if compared to placebo arm. Study drugs were well tolerated with no serious adverse events, the ramipril plus bisoprolol arm showed significantly more toxic effects and had a significantly higher rate of allocated treatment discontinuation as compared to the other arms. Conclusions: Cardioprotective pharmacological strategies in patients affected by BC receiving an anthracycline-based chemotherapy are well tolerated and seem to protect against cancer therapy-related LVEF decline and heart remodelling. Clinical trial information: NCT2236806 .